Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

SAVELLA (NDA-022256)

(MILNACIPRAN HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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08/18/2023 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Serotonin Syndrome

Additions and/or revisions underlined:

Selective-serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), including SAVELLA, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, tramadol, meperidine, methadone, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin i.e., MAOIs [see Contraindications (4), Drug Interactions (7)]. Serotonin syndrome can also occur when these drugs are used alone.

…

5.9 Increased Risk of Bleeding

Additions and/or revisions underlined:

Drugs that interfere with serotonin reuptake, including SAVELLA, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1)]. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

Inform patients about the increased risk of bleeding associated with the concomitant use of SAVELLA and NSAIDs, aspirin, or other drugs that affect coagulation [see Drug Interactions (7.7)].

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Nervous System Disorders ? anosmia, convulsions (including grand mal), hyposmia, loss of consciousness, …

7 Drug Interactions

DRUG INTERACTIONS

7.1 Monoamine Oxidase Inhibitors (MAOIs)

Additions and/or revisions underlined:

The concomitant use of SSRIs and SNRIs, including SAVELLA, with MAOIs increases the risk of serotonin syndrome. The use of MAOIs intended to treat psychiatric disorders with SAVELLA or within 5 days of stopping treatment with SAVELLA is contraindicated. The use of SAVELLA within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. In addition, do not initiate SAVELLA in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking SAVELLA, discontinue SAVELLA before initiating treatment with the MAOI [see Dosage and Administration (2.5, 2.6), Contraindications (4), Drug Interactions (7.1)].

7.2 Serotonergic Drugs

Additions and/or revisions underlined:

Serotonin syndrome can occur with use of SAVELLA and other serotonergic drugs (other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort), or with drugs that impair metabolism of serotonin (i.e., monoamine oxidase inhibitors). Advise patients of the signs and symptoms associated with serotonin syndrome and to seek medical care immediately if they experience these symptoms [see Dosage and Administration (2.5, 2.6), Warnings and Precautions (5.2)].

7.7 Drugs that Interfere with Hemostasis

Newly added section

Concomitant use of SAVELLA with an antiplatelet or anticoagulant drug (e.g., NSAIDs, aspirin, and warfarin) may potentiate the risk of bleeding. This may be due to the effect of SAVELLA on the release of serotonin by platelets. Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when SAVELLA is initiated or discontinued [see Warnings and Precautions (5.9)].

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.2)].

…

Clinical Consideration

Maternal adverse reactions

Use of SAVELLA in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.9)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Serotonin Syndrome

Inform patients about the risk of serotonin syndrome with use of SAVELLA as well as the increased risk when taken concomitantly with other serotonergic drugs including triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines and St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid) [see Warnings and Precautions (5.2), Drug Interactions (7.2)].

MEDICATION GUIDE

Newly added information:

Especially tell your healthcare provider if you take:

triptans used to treat migraine headache
medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, buspirone, SSRIs, SNRIs or MAOIs
tramadol, fentanyl, meperidine, methadone, or other opioids
amphetamines
the blood thinner warfarin (Coumadin, Jantoven)
non-steroidal anti-inflammatory drug (NSAID) (like ibuprofen, naproxen or aspirin)
over-the-counter supplements such as tryptophan or St. John’s Wort Ask your healthcare provider for a list of these medicines if you are not sure.

09/20/2021 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.12 Sexual Dysfunction

(Newly added subsection)

Use of SNRIs, including Savella, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1, 6.2)]. In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of Savella and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following additional adverse reactions have been identified from spontaneous reports of Savella received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to Savella. However, because these adverse reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events include:

Blood and Lymphatic System Disorders ? leukopenia, neutropenia, thrombocytopenia Cardiac Disorders ? supraventricular tachycardia, Takotsubo cardiomyopathy

Eye Disorders ? accommodation disorder Endocrine Disorders ? hyperprolactinemia Gastrointestinal Disorders ? acute pancreatitis Hepatobiliary Disorders ? hepatitis

Metabolism and Nutrition Disorders ? anorexia, hyponatremia Musculoskeletal and Connective Tissue Disorders ? rhabdomyolysis

Nervous System Disorders ? convulsions (including grand mal), loss of consciousness, Parkinsonism

Psychiatric Disorders ? aggression, anger, delirium, hallucination, homicidal ideation Renal and Urinary Disorders ? acute renal failure

Reproductive System and Breast Disorders ? galactorrhea, decreased libido, delayed or absent orgasm

Skin Disorders ? erythema multiforme, Stevens Johnson syndrome Vascular Disorders ? hypertensive crisis

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions underlined)

…

Sexual problems (dysfunction). Taking serotonin and norepinephrine reuptake inhibitors (SNRIs), including Savella, may cause sexual problems.

Symptoms in males may include

Delayed ejaculation or inability to have an ejaculation
Decreased sex drive

Problems getting or keeping an erection

Symptoms in females may include

Decreased sex drive

Delayed orgasm or inability to have an orgasm

Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with Savella. There may be treatments your healthcare provider can suggest.

…

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Sexual Dysfunction

Advise patients that use of Savella may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.12)].

…

12/19/2017 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Serotonin Syndrome

(Additions and/or revisions are underlined)

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Savella, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines…

If concomitant use of Savella with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines…

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

…These events include:

Cardiac Disorders - supraventricular tachycardia, Takotsubo cardiomyopathy

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Serotonin Syndrome

12/30/2016 (SUPPL-22)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Serotonin Syndrome

(Additions and/or revisions are underlined)

If concomitant use of Savella with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Serotonin Syndrome

Patients should be cautioned about the risk of serotonin syndrome with concomitant use of Savella with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid).

09/06/2016 (SUPPL-21)

Approved Drug Label (PDF)

6 Adverse Reactions

Postmarketing Experience

Addition of the following:

Gastrointestinal Disorders: acute pancreatitis